The herpesviruses are the largest and most complex of the known oncogenic DNA viruses. Cytomegalovirus, Epstein-Barr Virus, herpes simplex virus types 1 and 2 and varicella-zoster virus all have considerable clinical importance and persist as long-term latent infections associated with either neurones or lymphocytes in the majority of the human population. In this project we have set out to describe and compare the detailed structural organization of the genomes of these viruses. We especially hope to gain insights into the significance and function of the various tandem and inverted repetitive DNA sequences with regard to: (1) the evolutionary divergence of these viruses towards different disease states and tissue trophisms; (2) the signals and mechanisms used by herpesviruses to alter and regulate gene expression in te infected host cells and (3) the mechanisms of genome replication and persistence. Our current emphasis is in two directions: (A) A description of the structure of the genomes of two subgroups of primate cytomegaloviruses. Complete restruction enzyme cleavage maps and overlapping sets of fragments cloned in pBR322 plasmids have been constructed for CMV (Towne) and CMV (Colburn). The DNAs are totally different in structure and exhibit less than 1 percent cross-homology. CMV (Towne) DNA, but not CMV (Colburn) DNA, contains inverted repetitions and is organized into invertible L and S segments similar to those in HSV, although 50 percent larger in size. CMV (Colburn), but not CMV (Towne) DNA, cross-hybridizes to a highly repetitive cellular DNA sequence present in at least 10 to the 5th power copies in all mammalian genomes. (B) Attempts to study and modify the expression of individual cloned viral genes coding for immediate-early and delayed-early functions after short-term transfection procedures or in cell lines established after co-selection with the HSV thymidine kinase genes.